tbuckley/cabot-search huggingface dataset:
EPID-24. CAPTURING EVOLVING DEFINITIONS OF 12 SELECT RARE CNS TUMORS: A TIMELY REPORT FROM CBTRUS AND NCI-CONNECT
Authors: Mackenzie Price, Corey Neff, Carol Kruchko, Kristin Waite, Gino Cioffi, Jill Barnholtz-Sloan, Brittany Cordeiro, Marta Penas-Prado, Byram Ozer, Patrick Cimino, Mark Gilbert, Terri Armstrong, Quinn Ostrom
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Incidence, prevalence, and survival are population-based cancer statistics that describe cancer burden. The National Cancer Institute’s Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) specializes in research of 12 rare CNS tumor types to improve approaches to care and treatment. These tumors include atypical teratoid/rhabdoid tumors, brainstem and midline glioma, choroid plexus tumors, ependymoma, high grade meningioma, gliomatosis cerebri, medulloblastoma, oligodendroglioma/anaplastic oligodendroglioma, pineal region tumors, pleomorphic xanthoastrocytoma, CNS embryonal tumors, not elsewhere classified (NEC)/not otherwise specified (NOS), and primary CNS sarcoma. This study aimed to update incidence, prevalence, and survival statistics for these tumors. METHODS The Central Brain Tumor Registry of the United States (CBTRUS) database, a combined dataset of CDC’s National Program of Cancer Registries (NPCR) and NCI’s Surveillance, Epidemiology and End RESULTS (SEER) data, was used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race-ethnicity, and age (2008-2019). NPCR data were used to calculate relative survival (RS) estimates (2008-2018). Prevalence on December 31, 2019 was estimated using annual age-specific incidence and survival from CBTRUS and SEER, respectively. RESULTS AAAIR was 1.51 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAAIR=0.41/100,000). Most tumor types were more common in males, adults (ages 40+ years) or children ages &amp;lt; 15 years, and non-Hispanic White individuals. Ependymomas were most prevalent (19,339 cases) followed by oligodendrogliomas (15,070 cases). RS for all subtypes combined at 1-, 5-, and 10-years was 86.6%, 71.9%, and 65.3%, respectively. Ependymomas had the highest RS (5-years=90.6%) and primary CNS sarcomas had the lowest RS (5-years=7.7%). CONCLUSIONS Incidence, prevalence, and survival patterns for these 12 selected rare cancer subtypes varied significantly by type. Population-based data are critical to guiding effective design of and accrual expectations for clinical trials in rare cancers.
EXTH-58. USING MEK INHIBITOR TO ENHANCEMENT 5-ALA MEDIATED SONODYNAMIC THERAPEUTIC EFFECT: A PRECLINICAL STUDY
Authors: Chiungyin Huang, Kuo-Chen Wei
Journal: Neuro-Oncology (2023)

Abstract The potential of sonodynamic therapy (SDT) using sono-sensitive molecules such as 5-aminolevulinic acid to treat brain tumor is highly noted for glioma treatment. However, the accumulation of 5-ALA in glioma cells is limited by the heterogeneous cell types of GBM. MEK inhibitor is known to be effective on enhance the accumulation of 5-ALA in glioma cells, therefore, we aim to study the effect of MEK inhibition on sonodynamic therapy. MEK inhibitor trametinib were systemically administered to animals bearing subcutaneous tumor xenograft 24 hours prior to treatment. Subsequently, the effects of 5-ALA-mediated sonodynamic therapy were determined by measuring the volume of tumor xenografts and the bodyweights animals. Glioma cells and tissue samples were collected, and the effect on MEK signaling pathway were evaluated by immunohistochemistry/PCR/Western blotting. For tumor growth data, comparison across multiple groups was performed with repeated measures two-way analysis of variance (ANOVA). Animals were divided into 5 groups: control, focused ultrasound (0.35 MPa.duty10%.10min), trametinib (1mg/kg), 5ALA (180mg/Kg) +FUS, trametinib(1mg/Kg)+5ALA(180mg/Kg) +FUS (n = 5 for each group). Following treatment, tumor growth was monitored by digital caliper twice a week. As compared with control group, the tumor size of trametinib+5ALA+FUS group is significantly less than control group (p = 0.0085, 0.0001 and 0.0255 at day 4, 7 and 11). No significant difference was observed in other groups verse control. The daily mice body weight records revealed no significant change, demonstrated no major toxicity was induced by the MEK inhibitor/5-ALA/sonodynamic combination treatment. Our study demonstrates that suppression of MEK pathway by MEK inhibitor trametinib significantly increase the accumulation of PpIX. In tumor animal models, mice pretreated with MEK inhibitor presented favorable response to 5-ALA mediated sonodynamic therapy. Our finding may suggest a new strategy to enhance the effect of sonodynamic therapy.
DDEL-02. CLINICAL BENEFIT OF BEVACIZUMAB AND IRINOTECAN (BEV+IRI) IN PATIENTS WITH RELAPSED/REFRACTORY GLIOBLASTOMA (R/RGBM) AND ITS POTENTIAL PREDICTORS
Authors: Ji Hyun Park, Kyung Rae Cho
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND/AIM: Bevacizumab-containing chemotherapy constitutes an important salvage treatment for recurrent/refractory glioblastoma(r/rGBM). Patients and methods: We retrospectively collected the data of r/rGBM patients treated with the combination of bevacizumab and irinotecan (BEV+IRI) as their salvage treatment from July 2013 and December 2021 in Konkuk Medical Center of Korea. Patients with available results from molecular diagnostic tests were eligible, and markers of interest were examined including the presence of MGMT methylation, IDH1/2 mutation, or 1p/19q co-deletion. Efficacy of BEV+IRI and its potential biomarker was explored. RESULTS: Among 21 patients, 38.1% demonstrated European Cooperative Oncology Group-Performance scale (ECOG-PS) ≥3. The majority (71.4%) received BEV+IRI as their second-line chemotherapies, and the median dose was 5 (range=1-25). Objective response rate (ORR) was 33.3% and disease-control rate (DCR) was 85.7%. Irrespective of objective response, early clinical response was achieved in 14(66.7%) patients. During the median follow-up of 16.4 months for survivors, median progression-free survival (PFS) and overall survival (OS) were 3.6 and 6.8 months, respectively. ECOG PS≥3 and TP53 loss were independent predictors of an unfavorable OS, while prompt clinical improvement could predict favorable OS. Any molecular aberration was associated with OS or PFS in the study. CONCLUSION: Salvage BEV+IRI treatment in r/rGBM conferred comparable clinical benefit. ECOG PS ≥3, TP53 loss, and lack of prompt clinical improvement after the treatment were significantly associated with an unfavorable OS.
IMMU-43. IN-DEPTH SINGLE-CELL ANALYSIS OF THE IMMUNE LANDSCAPE IN CHORDOMAS REVEALS T-CELL EXHAUSTION AND INFORMS RATIONAL IMMUNOTHERAPEUTIC INTERVENTION
Authors: Victor Arrieta, Jasim K Benotmane, Junfei Zhao, Silpol Dhiantravan, David Hou, Joshua Katz, Si Wang, Brandyn Castro, Surya Pandey, Meghan Cholak, Kirstyn Galbraith, Hinda Najem, Yu Han, Chetan Bettegowda, Matija Snuderl, Craig Horbinski, Jason Miska, Roger Stupp, Amy Heimberger, Maciej Lesniak, Adam Sonabend, Jean-Paul Wolinsky, Dieter Henrik Heiland, Catalina Lee-Chang
Journal: Neuro-Oncology (2023)

Abstract Chordomas are rare tumors that arise from remnants of the notochord. The standard of care for chordoma remains only surgery and radiotherapy. Though checkpoint inhibition therapy shows promise, recent immunotherapy trials failed to reach endpoints. This emphasizes the need to comprehensively understand the tumor and peripheral immune landscape of chordomas to establish a rationale for immunotherapeutic intervention. Here, we aimed to investigate the composition and functionality of the tumor and peripheral immunological landscape of chordomas using single-cell RNA-sequencing, TCR profiling, and multiplex immunofluorescence. We generated a comprehensive single-cell atlas of chordomas incorporating paired single-cell transcriptomic samples from the tumor and blood of five patients and single-cell TCR sequencing data to analyze the T-cell clonality. Furthermore, we analyzed and quantified the immune cell composition (CD3+, CD4+, CD8+, CD20+, and CD163+ cells) of 33 chordomas (14 clival and 19 spinal) through multiplex immunofluorescence. Our findings revealed that the CD8+ T-cell antitumoral immunity originates in the periphery, characterized by clonal expansion of cytotoxic and memory T cells in the blood. However, this immunity undergoes progressive exhaustion following tumor infiltration. Furthermore, we observed that CTLA-expressing central memory and Tregs constitute most of the CD4 T-cell tumoral landscape. Within the B cell compartment, regulatory B cells and plasma cells were the most abundant. Hierarchical clustering analysis of 33 chordomas identified 3 distinct clusters based on the relative abundance of T cells, B cells, and macrophages. Notably, a higher abundance of CD3+ T cells was found in newly diagnosed chordomas as opposed to recurrent cases. Our study provides crucial insights into the complex immune landscape of chordoma. The results of this work may be of foundational importance to understanding chordoma immunology and tailoring immunotherapeutic strategies for these tumors.
NIMG-08. ANALYSIS OF11C-METHIONINE PET UPTAKE AND PROGNOSIS IN LOWER GRADE GLIOMAS
Authors: Kaoru Tamura, Motoki Inaji, Toshihiro Yamamura, Shoko Hara, Kazuhide Shimizu, Yoji Tanaka, Tadashi Nariai, Kenji Ishii, Taketoshi Maehara
Journal: Neuro-Oncology (2023)

Abstract PURPOSE The 2021 WHO Classification of Tumors of the Central Nervous System incorporates molecular alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. This study aimed to assess the correlation between 11C-methionine uptake, molecular features and prognosis in newly diagnosed lower-grade gliomas (LGGs). METHODS 93 newly diagnosed LGG patients (Grade 2: 39 patients, Grade 3: 54 patients) who underwent surgery at Tokyo Medical and Dental University Hospital from 2000 to 2020 and imaged preoperatively using 11C-methionine PET were retrospectively included in this study. These patients were re-classified according to the 2021 WHO classification. The tumor-to-normal ratio (T/N) of 11C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. RESULTS 44 out of 93 gliomas were IDH wild-type tumors and re-classified as glioblastoma or pediatric-type gliomas according to the 2021 WHO classification and therefore excluded from the analysis. Remaining 49 LGGs were re-classified in two types- Oligodendrogliomas, IDH-mutant and 1p/19q- codeleted (n=25), and Astrocytomas, IDH-mutant (n=24)- following the indications provided by the 2021 WHO classification. The median T/N ratio in Oligodendrogliomas, IDH-mutant and 1p/19q- codeleted were 1.83 in grade 2 and 2.83 in grade 3, which were significantly higher than those in Astrocytoma, IDH-mutant (grade2: 1.38, grade3:1.62). Kaplan–Meier survival analysis revealed that Oligodendroglioma, IDH-mutant and 1p/19q- codeleted had significantly better outcomes regardless of WHO grade. CONCLUSION The results indicated that LGG categories reclassified with molecular classification correlate with the T/N ratio of methionine uptake and the prognosis.
CTNI-61. MYCOPHENOLATE MOFETIL INHIBITS GLIOBLASTOMA PURINE METABOLISM IN HUMANS: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Yoshie Umemura, Wajd Al-Holou, Ameer Elaimy, Andrew J Scott, Denise Leung, Nathan Clarke, Michelle M Kim, Sean Ferris, Jennifer Thomas, Jason Heth, Matthew Schipper, Krithika Suresh, Theodore Lawrence, Daniel Wahl
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Mycophenolate mofetil (MMF), a purine synthesis inhibitor, improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) is the first-in-human study to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. METHODS Adult patients meeting eligibility are given MMF 500-2000 PO BID using TITE-CRM dose assignment. Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly-diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with chemoradiation and followed for 28 days for DLT1-period. During the adjuvant temozolomide (days 1-5/28-day cycle) period, MMF is given days 0-5 on a separate dose-escalation (DLT2 period = cycles 1-2). Tissues from phase-0 recurrent glioblastoma patients (N = 8) receiving MMF 500-2000mg BID one-week pre-operatively are analyzed using mass spectrometry. RESULTS Enhancing and non-enhancing tumor from phase 0 subjects yielded above 1 µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p = 0.009), indicating effective target engagement and inhibition of purine synthesis. No DLT has been observed with adjuvant cyclic temozolomide in phase 1 newly-diagnosed group (N = 26), nor in the recurrent-disease group (N = 18) with re-irradiation. In newly diagnosed arm, 3 subjects experienced DLT1 at 2000mg BID; grade-3 hemiparesis and cognitive disturbance, and grade-4 thrombocytopenia. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1. CONCLUSION MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary promising evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.
STEM-17. IMPLICATING ASTROCYTE PROGENITOR SIGNATURES FROM THE DEVELOPING HUMAN SUBVENTRICULAR ZONE IN GLIOBLASTOMA PROGRESSION AND RECURRENCE
Authors: Susana Isabel Ramos, Wan Sze Chang, Elena Zaslavsky, Nadejda Tsankova
Journal: Neuro-Oncology (2023)

Abstract Although astrocyte-like progenitors in the adult subventricular zone (SVZ) have been put forward as the glioblastoma (GBM) cell of origin, the mechanisms that trigger astrogenesis in the developing SVZ are poorly understood. We previously reconstructed astrocyte lineages using computational tools and identified PDGFRβ+ astrogenesis-committed radial glia (RG-A) and EGFR+ gliogenic intermediate progenitor cells (gIPCs). We have, however, yet to identify the transcription factors (TFs) that drive the differentiation of these progenitors in the pre- and postnatal SVZ. As malignant cells are known to co-opt neurodevelopmental pathways, the exploitation of TF driver vulnerabilities in malignant cells could bring novel therapeutic strategies to hinder GBM progression or recurrence. Here, we integrated single nucleus RNA- (snRNA-seq) and ATAC-sequencing (snATAC-seq) datasets from 1) surgically resected GBMs (n = 5), 2) the subventricular zone and neocortex from non-pathological adult cortices (n = 3) and 3) the corresponding germinal matrix and cortical plate of non-pathological cortices ranging from 17 to 41 gestational weeks (n = 17) and 21 to 301 postnatal days in age (n = 9). To prioritize candidate drivers of astrogenesis computationally, we correlated motif enrichment with gene expression over pseudotime in gIPC and RG-A lineages. Subsequently, we projected transcriptional signatures from non-pathological neocortices onto GBMs. Interestingly, we observed high proportions of tumor cells with preferentially enriched prenatal gIPC-like signature in EGFR amplified GBMs and with preferentially enriched postnatal RG-A-like signature in GBMs with PFGFRα or FGFR3 amplification. As tumor recurrence is associated with a mesenchymal-like switch, we were intrigued to find that RG-A-like cells exhibited a mesenchymal-like phenotype in a recurrent GBM. Currently, we are developing an in vitro assay to manipulate the expression of astrogenic drivers and force the differentiation of patient-derived, primary GBM cells into astrocytes; a strategy that we will later apply in patient-derived xenograft models.
RADT-14. ROLE OF CHEMOTHERAPY AFTER RADIATION THERAPY FOR GYNECOLOGIC METASTASES TO THE BRAIN
Authors: Eric Chen, Todd Aquino-Michaels, Sadhvi Batra, Riley Lochner, Anthony Rizzo, Graham Chapman, Ravi Kyasaram, Eleanor Harris, Tiffany Hodges, Lindsay Ferguson, Serah Choi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Brain metastasis from gynecologic malignancy is rare, and the optimal treatment is undetermined. METHODS Retrospective data was collected at a single institution from 2001-2021 on 66 patients with brain metastasis from gynecologic malignancy who underwent brain radiation therapy (RT). Kaplan-Meier survival analyses, long-rank tests, and a multivariate proportional hazards model were performed. RESULTS Median overall survival (OS) and intracranial progression-free survival (PFS) were 4.3 and 3.6 months, respectively. 25 (38%) patients started chemotherapy after RT in a median 32.5 days (IQR 12-53). Compared to those who did not start chemotherapy after RT, those who did had a longer median OS (9.8 vs 2.6 months, p &amp;lt; 0.01) and PFS (5.0 vs 2.5 months, p = 0.01). On univariate analysis, factors associated with worse survival included &amp;gt;10 brain metastases (p = 0.09), leptomeningeal involvement (p &amp;lt; 0.01), presence of extracranial disease (p = 0.01), no receipt of surgery (p = 0.05), receipt of whole brain RT (p &amp;lt; 0.01), and no receipt of chemotherapy after RT (p &amp;lt; 0.01). On multivariate analysis including above factors and age-adjusted Charlson Comorbidity Index, only receipt of chemotherapy after RT was significantly associated with improved survival (HR 0.32, CI 0.16-0.64). The most common chemotherapy was platinum-based agents in 10 (40%) patients, with no difference in survival (p = 0.74) between those treated with platinum-based versus other agents. More patients who started chemotherapy after RT compared to those who didn’t had ovarian cancer (56 vs 22%, p = 0.02), underwent surgery (52 vs 29%, p = 0.07), and underwent stereotactic radiosurgery (SRS) (64 vs 27%, p &amp;lt; 0.01). For patients who did vs did not receive chemotherapy after SRS, median OS was 11.3 vs 4.3 months (p = 0.01), and after WBRT 4.5 vs 2.2 months (p = 0.10). CONCLUSION Patients treated with chemotherapy after SRS in this population may have improved outcomes, though prognosis remains poor.
ANGI-11. MOLECULAR MECHANISM OF TARGETING EPITHELIAL MEMBRANE PROTEIN-2 IN MALIGNANT MENINGIOMAS
Authors: Isaac Yang, Mahlet Mekonnen, Anubhav Chandla, Brian Aguirre, Madhuri Wadehra
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Meningiomas comprise approximately one-third of all primary central nervous system neoplasms. While many meningiomas remain benign, as many as 35% of meningiomas are graded as atypical or anaplastic/malignant with a 5-y survival rate as low as 35%. Targeting the tetraspan protein epithelial membrane protein-2 (EMP2)-HIF1α pathway through EMP2 knockdown may inhibit tumor growth, invasion, and neoangiogenesis in malignant meningioma. METHODS In collaboration with the UCLA Brain Tumor SPORE, we gathered a panel of malignant meningiomas (IOMM-LEE, CH157). To determine the function of EMP2, we created EMP2 vector control and knockdown models in both cell lines and analyzed the cells by RNA sequencing, transcriptomic functional analysis, and migration assay. RESULTS Gene functional analysis enriched for biological processes showed that knockdown of EMP2 inhibited multiple malignant pathways in these meningioma cells including the response to hypoxia, cell proliferation, invasion, and stem cell maintenance. Further analyses of EMP2 expression with other differentially expressed genes of interest revealed that VEGFA expression significantly decreased when EMP2 is knocked down (p&amp;lt; 0.001). Moreover, cellular migration and invasion regulated by EMP2 were tested in control and EMP2 knockdown malignant cells using a scratch assay, where knockdown of EMP2 reduced the rate of cell invasion by 50% (p = 0.0003). Additionally, anti-EMP2 mAb treatment in the control malignant cell line significantly reduced EMP2-mediated signal transduction (p = 0.0031). CONCLUSIONS Our study is the first to demonstrate the modulation of EMP2 and its implications in malignant meningioma pathogenesis, VEGFA-HIF1α pathway, and stem cell regulation. Targeting EMP2 may result in therapeutic benefits for malignant meningioma.
STEM-11. A GLIOBLASTOMA SINGLE-CELL META-ATLAS IDENTIFIES NOVEL NEUROVASCULAR PROGENITOR IN TUMORS
Authors: Elisa Fazzari, Daria Azizad, Matthew Li, Weihong Ge, Nicholas Bayley, Christopher Tse, Andrew Tum, David Raleigh, Kunal Patel, Elizabeth Crouch, David Nathanson, Aparna Bhaduri
Journal: Neuro-Oncology (2023)

Abstract Glioblastomas (GBM) are defined by cell type heterogeneity that underlies treatment resistance and brain invasion. Recent studies have identified reactivation of neurodevelopmental cells and gene expression programs in GBM. Here, we leverage a neurodevelopmental perspective to identify novel gene signatures in GBM. To do so, we assembled a glioblastoma meta-atlas comprised of 73,376 single-cell transcriptomes from 7 published studies. With these data, we developed a novel module generation strategy to mitigate batch effects, enabled analysis of signatures in each tumors, and emphasized modules observed across multiple tumors. Using this approach, we validated known tumor cell types and axes of variation, and also identified novel stemness programs that were uniquely expressed across distinct progenitor populations. Within progenitor subtypes, we identified a neurovascular progenitor (NVP) of cells expressing a mixed vascular signature including genes characteristic of mural and endothelial identity as well as transcriptional programs reminiscent of neural stem cells. Although tumor associated or glioma stem cell derived vasculature has been described as important for tumor formation and progression, the NVP appears to be stem-like. To our knowledge, this population has not been described in GBM. We validated the existence of this NVP with immunofluorescence and fluorescent activated cell sorting from patient tumors followed by single-cell RNA-sequencing. Using a novel organoid transplantation model, we employed single-cell lineage barcoding to identify the progeny of patient-derived NVP cells, determining that they result in various cell types with diverse morphologies. Exploration of data from more traditional model systems including gliomaspheres and mouse GBM models indicate preservation of this NVP identity across systems. We hypothesize that NVP cells may play important roles in tumor plasticity, and thus may be a valuable therapeutic target to explore.